Regulation of Placental Vascular Endothelial Growth/Permeability Factor Expression and Angiogenesis by Estrogen during Early Baboon Pregnancy

We have recently shown that there was a developmental increase in placental trophoblast vascular endothelial growth/permeability factor (VEG/PF) expression and vascularization that closely paralleled maternal serum estrogen levels during advancing baboon gestation. The present study determined whether estrogen regulates these important aspects of primate development. VEG/PF mRNA levels were determined by competitive RT-PCR in isolated villous placental cells, and placental vascularization was assessed by image analysis. Placentas were obtained on d 60 of gestation (length of gestation is 184 d) from baboons in which estrogen levels on d 25–59 were increased by daily administration of aromatizable androstenedione or decreased by aromatase inhibitor CGS 20267. Androstenedione treatment increased maternal serum estradiol levels 3-fold (P < 0.01) and placental villous cytotrophoblast VEG/PF mRNA level to a value (mean ± se, 26,836 ± 5,625 attomoles/μg total RNA) 2.5-fold greater (P < 0.05) than that in untreated animals (11,645 ± 1,746 attomoles/μg RNA). In contrast, administration of CGS 20267 decreased serum estradiol (P < 0.01) and placental cytotrophoblast mRNA (2,912 ± 693 attomoles/μg RNA; P < 0.05) levels by 75%, effects prevented by concomitant administration of CGS 20267 and estradiol. VEG/PF mRNA levels in inner villous cells were unaltered. Coinciding with the increase in placental VEG/PF expression, the percent vascularized area (3.46 ± 0.23) and vessel density (493 ± 34 vessels/mm2) of the villous placenta in untreated baboons on d 60 were increased (P < 0.01) in baboons in which estrogen levels were elevated by androstenedione treatment (6.54 ± 0.56 and 743 ± 27 vessels/mm2, respectively). It is concluded that estrogen has an important role in stimulating trophoblast VEG/PF expression and consequently villous placental angiogenesis to promote fetal growth and development in early primate pregnancy.